Linear Mixed-effects Regression Analysis Research Articles

The potential role of frailty in modifying quality-of-life related outcomes in metastatic castration-resistant prostate cancer (mCRPC) patients receiving docetaxel, abiraterone, enzalutamine, and radium 223.

63 Background: As the arsenal of therapeutic agents for mCRPC expands, frailty-informed care is emerging as a strategy for tailoring management decisions. Yet, data to guide this approach and to ascertain its impact on the mood, fatigue, pain, and quality of life (QoL) experienced by older men with mCRPC remain lacking. We examined patient-reported outcomes, stratified by a validated frailty index (FI), for mCRPC treatment with docetaxel chemotherapy (CHEMO), abiraterone (ABI), enzalutamide (ENZA), or radium 223 (RAD). Methods: Older (aged 65+) men starting one of four approved therapies for mCRPC were enrolled in a multicenter prospective cohort study. Assessing their mood, fatigue, pain, and QoL with PHQ-9, ESAS tiredness, ESAS pain, and FACT-G total as well as subscale scores, we used linear mixed effect models to determine change in each outcome over time (0, 3, 6 months). At end of treatment, we administered the Decisional Regret Scale. We then constructed a FI from 34 variables that span laboratory abnormalities, geriatric syndromes, instrumental activities of daily living, social support, as well as emotional, cognitive, and physical deficits. Following established cut-offs, we categorized patients as non-, pre-, and frail, then performed stratified linear mixed effects regression analyses to identify differences in outcomes by frailty status. Results: A total of 198 men (mean age 75.1) starting CHEMO (n = 70), ABI (n = 38), ENZA (n = 67), and RAD (n = 29) were included, of which 9.6%, 1.5%, 5.6%, and 2.5%, respectively, were determined frail. Frailty correlated only modestly with age (Pearson r = 0.27). Independent of frailty status, patients across treatment cohorts were similar in terms of baseline QoL-related measures, with the exceptions of mood (p = 0.033) and pain (p = 0.034). Over time, no significant change in QoL was reported, although all four therapies resulted in generally low levels of decisional regret and similar trends of improved pain but worsened mood (p = 0.006 and 0.02, respectively). At baseline, frailty status correlated with worse FACT-G total (p < 0.001) and functional well-being (p < 0.001), as well as worse depression scores (p < 0.001). According to FI-stratified analysis, frail patients experienced similar QoL-related outcomes to fit patients for all measures aside from mood (p < 0.001). Contrary to our hypotheses, frailty was not associated with significant worsening in emotional well-being or functional well-being in response to mCRPC treatment. Conclusions: Of the older men receiving care for mCRPC, frail patients may experience generally similar trends in QoL as fit patients. Interestingly, frailty status, rather than treatment modality, may play more of a contributory role to changes in QoL-related outcomes over time.

Interaction effect of neighborhood walkability and season on adults’ step count

IntroductionWalking activity shows differences by season or neighborhood walkability (NW). Elucidation of interactions between season and NW may contribute to the identification of high-risk populations. We examined the interaction effect of objectively measured NW and season on step counts in a large population. MethodsWe analyzed consecutively measured pedometer data collected from 47,233 adults aged 40–79 years who participated in the Yokohama Walking Point Program. Step counts in May 2018 (spring) and August (summer) as well as October (autumn) and January 2019 (winter) were compared. Neighborhoods (postal code areas) were classified into quartiles for each of the three NW variables (i.e., distance to the nearest railway station, population density, and street intersection density). The interaction effect of each of the NW variables and season on step count was examined using mixed-effects linear regression analyses. ResultsThe average daily step counts were fewer in summer and winter and higher in areas near the railway stations and areas with higher population density. We found a significant interaction effect of NW and season on step counts in summer. Participants residing in areas farther from the nearest railway station (P < 0.001) or areas with the lowest quartile of population or intersection density (P = 0.001, 0.030, respectively) showed a decline in step counts in summer by up to 118.4 steps/day compared with participants in other areas, which was not found when comparing the step counts between winter and autumn. ConclusionsNW and season showed interaction effect on adults’ step counts, indicating that in low walkable areas where residents generally walk less, their step counts decrease more in summer when compared with those in other areas; however, this was not the case in winter. Promoting walking in the less walkable neighborhoods, specifically during summer, is required.

Impact of expression mode and timing of sample collection, relative to milk ejection, on human milk bacterial DNA profiles.

To investigate the impact of expression mode: electric breast pump or hand expression, and timing of sample collection: pre- and post-milk ejection on human milk (HM) bacterial DNA profiles. Three HM samples from the same breast were collected from 30 breastfeeding mothers: a pre-milk ejection pump-expressed sample (pre-pump), a post-milk ejection pump-expressed sample (post-pump) and a post-milk ejection hand-expressed sample (post-hand). Full-length 16S rRNA gene sequencing was used to assess milk bacterial DNA profiles. Bacterial profiles did not differ significantly based on mode of expression nor timing of sample collection. No significant differences were detected in the relative abundance of any OTUs based on expression condition (pre-pump/ post-pump and post-pump/post-hand) with univariate linear mixed-effects regression analyses (all P-values>0·01; α=0·01). Similarly, no difference in richness was observed between sample types (number of observed OTUs: post-pump/post-hand P=0·13; pre-pump/post-pump P=0. 45). Bacterial DNA profiles of HM did not differ according to either expression method or timing of sample collection. Hand or pump expression can be utilized to collect samples for microbiome studies. This has implications for the design of future HM microbiome studies.

Prostatic Urethral Lift in Patients With Obstructive Median Lobes: A Single Surgeon Experience at an Academic Center

ObjectiveTo examine the long-term efficacy of prostatic urethral lift (PUL) for treating men, with or without an obstructive median lobe (OML), who suffer from lower urinary tract symptoms attributed to benign prostatic hyperplasia. Materials and MethodsA retrospective review was performed on all consecutive PUL cases with or without OML from October 2017 to November 2019 by a single academic surgeon. Outcomes were measured using the International Prostate Symptoms Survey (IPSS) with quality of life (QoL) scores. Comparative testing and mixed-effects linear regression analysis were utilized with significance set at α = 0.05 and performed with Stata (College Station, TX). ResultsA total of 110 PUL procedures were performed on 106 patients (4 repeat surgeries) with a median age of 66.5 (interquartile range: 60.4-73.7). Twenty-three patients (21.7%) had an OML. Following PUL, patients in both groups showed significant improvements in IPSS (P <.001) and QoL (P <.001) scores. When stratifying by OML and controlling for confounding, IPSS scores in both groups displayed statistically significant improvement at follow-up visits, with no statistically significant intergroup difference (P = .32). The same held true for QoL improvements, with no statistically significant difference between groups (P = .18). The presence of an OML resulted in minimal effects on perioperative outcomes and complications but required significantly more implants (P = .008). ConclusionPUL is a minimally invasive procedure effective at reducing lower urinary tract symptoms and improving the lives of men with benign prostatic hyperplasia without incurring risks of serious complications. These improvements were equivalent and upheld in patients who presented with OML.

From biomechanics to pathology: predicting axonal injury from patterns of strain after traumatic brain injury.

The relationship between biomechanical forces and neuropathology is key to understanding traumatic brain injury. White matter tracts are damaged by high shear forces during impact, resulting in axonal injury, a key determinant of long-term clinical outcomes. However, the relationship between biomechanical forces and patterns of white matter injuries, associated with persistent diffusion MRI abnormalities, is poorly understood. This limits the ability to predict the severity of head injuries and the design of appropriate protection. Our previously developed human finite element model of head injury predicted the location of post-traumatic neurodegeneration. A similar rat model now allows us to experimentally test whether strain patterns calculated by the model predicts in vivo MRI and histology changes. Using a controlled cortical impact, mild and moderate injuries (1 and 2 mm) were performed. Focal and axonal injuries were quantified with volumetric and diffusion 9.4 T MRI at 2 weeks post injury. Detailed analysis of the corpus callosum was conducted using multi-shell diffusion MRI and histopathology. Microglia and astrocyte density, including process parameters, along with white matter structural integrity and neurofilament expression were determined by quantitative immunohistochemistry. Linear mixed effects regression analyses for strain and strain rate with the employed outcome measures were used to ascertain how well immediate biomechanics could explain MRI and histology changes. The spatial pattern of mechanical strain and strain rate in the injured cortex shows good agreement with the probability maps of focal lesions derived from volumetric MRI. Diffusion metrics showed abnormalities in the corpus callosum, indicating white matter changes in the segments subjected to high strain, as predicted by the model. The same segments also exhibited a severity-dependent increase in glia cell density, white matter thinning and reduced neurofilament expression. Linear mixed effects regression analyses showed that mechanical strain and strain rate were significant predictors of in vivo MRI and histology changes. Specifically, strain and strain rate respectively explained 33% and 28% of the reduction in fractional anisotropy, 51% and 29% of the change in neurofilament expression and 51% and 30% of microglia density changes. The work provides evidence that strain and strain rate in the first milliseconds after injury are important factors in determining patterns of glial and axonal injury and serve as experimental validators of our computational model of traumatic brain injury. Our results provide support for the use of this model in understanding the relationship of biomechanics and neuropathology and can guide the development of head protection systems, such as airbags and helmets.

Measurement Reactivity of Accelerometer-Based Sedentary Behavior and Physical Activity in 2 Assessment Periods.

The purposes of this study were to examine accelerometer measurement reactivity (AMR) in sedentary behavior (SB), physical activity (PA), and accelerometer wear time in 2 measurement periods and to quantify AMR as a human-related source of bias for the reproducibility of SB and PA estimates. In total, 136 participants (65% women, mean age = 54.6y) received 7-day accelerometry at the baseline and after 12months. Latent growth models were used to identify AMR. Intraclass correlations were calculated to examine the reproducibility using 2-level mixed-effects linear regression analyses. Within each 7-day accelerometry assessment, the participants increased their time spent in SB (b = 2.4min/d; b = 3.8min/d) and reduced their time spent in light PA (b = -2.0min/d; b = -3.2min/d), but did not change moderate to vigorous PA. The participants reduced their wear time (b = -5.2min/d) only at the baseline. The intraclass correlations ranged from .42 for accelerometer wear time to .74 for SB. The AMR was not identified as a source of bias in any regression model. AMR may influence SB and PA estimates differentially. Although 7-day accelerometry seems to be a reproducible measure, our findings highlight accelerometer wear time as a crucial confounder in analyzing SB and PA data.

Work e-mail after hours and off-job duration and their association with psychological detachment, actigraphic sleep, and saliva cortisol: A 1-month observational study for information technology employees.

ObjectiveA sufficient duration of time off after work is necessary to ensure workers’ health. Better quality of off‐job time can also facilitate recovery from fatigue, but its quantitative influence is largely unknown. We aimed to examine how off‐job time quality (as measured by the frequency of emailing after work), and off‐job duration is associated with psychological detachment, actigraphic sleep, and saliva cortisol using a 1‐month observational study.MethodsThe participants were 58 daytime employees working at an information technology company. Sleep actigraphy and saliva cortisol as well as self‐reported outcomes were repeatedly measured for 1 month. Two‐way (work e‐mail frequency × off‐job time) multilevel mixed‐effects linear regression analyses were performed in both continuous and categorical variables.ResultsThe frequency of work e‐mailing after hours was significantly associated with self‐reported outcomes and actigraphic sleep quality, while a significant association was not found in cortisol awakening responses and actigraphic sleep duration. A significantly larger cortisol response after awakening was found in shorter, rather than longer, durations of off‐job time. Self‐reported detachment, rumination and carry‐over fatigue showed significant interactions between work e‐mail and off‐job time, suggesting that worse outcomes were found in a higher frequency of work e‐mail even when employees had longer amounts of off‐job time.ConclusionOur findings suggest that ensuring the quality and duration of off‐job time is beneficial for recovery from work with sufficient sleep. Specifically, the frequency of e‐mailing after work should be minimized to make recovery complete.

Relationship between the frequency of electrocautery of Hunner lesions and changes in bladder capacity in patients with Hunner type interstitial cystitis

Electrocautery is a promising treatment option for patients with Hunner type interstitial cystitis (HIC), but frequently requires multiple sessions due to recurrence of the lesions. In the present study, we assessed the relationship between the frequency of electrocautery of Hunner lesions and changes in maximum bladder capacity (MBC) at hydrodistension in a large cohort of 118 HIC patients. Three mixed-effect linear regression analyses were conducted for MBC against (1) the number of sessions; (2) the number of sessions and the time between each session and the first session; and (3) other relevant clinical parameters in addition to the Model (2). The mean number of sessions was 2.8 times. MBC decreased approximately 50 mL for each additional electrocautery session, but this loss was offset by 10 mL for each year the subsequent session was postponed. MBC of < 400 mL at the first session was a significant risk factor for MBC loss with further sessions. No other clinical parameters were associated with MBC over time. This study demonstrates a significant relationship between the frequency of electrocautery of Hunner lesions and MBC changes in HIC patients. Low MBC at the first session is a poor prognostic marker for MBC loss over multiple sessions.

Total cholesterol concentration predicts the effect of plasmapheresis on hypertriglyceridemic acute pancreatitis: a retrospective case\u2013control study

BackgroundWhat kind of patients with hypertriglyceridemic acute pancreatitis (HLAP) might benefit from plasmapheresis (PP) remains unknown. The objective of this study is to determine the predict function of total cholesterol (TC) on the Triglyceride (TG)-lowing effect in patients on either non-PP or PP therapy.MethodsPatients were categorized into high total cholesterol (HTC)/low total cholesterol (LTC) groups based on TC level of 12.4 mmol/L. The primary outcome was TG reduction to below 500 mg/dL within 48 h. Linear mixed-effect model and logistic regression analyses were used to assess the association of TC level and TG-lowing efficacy in different therapy groups.ResultsCompared with LTC group, patients with HTC showed more severe imaging manifestations (p < 0.001) and higher APACH II scores (p = 0.036). Deaths occurred only in HTC groups. Significant interaction of time sequence with the 2 TGs-lowing therapy groups on TG level was only found in HTC group (p < 0.001). In patients with elevated TC level, primary outcome occurred in 66.67% of patients in the PP group, and 27.91% in the non-PP group. After adjustment for age, gender, CT grade and APACH II score, the odd ratio remain significant (OR 5.47, 95% confidence interval [CI] 1.84–16.25, p = 0.002). Furthermore, in patients with lower TC level, no significant difference was found in primary outcome between PP group and non-PP group (81.25% versus 62.30%, adjusted OR 2.05; 95% CI 0.45–9.40; p = 0.353).ConclusionsTC could be a potential biomarker to predict the effects of TG-lowing therapy in patients with HLAP.

Do morally injurious experiences and index events negatively impact intensive PTSD treatment outcomes among combat veterans?

ABSTRACT Background: It has been suggested that current frontline posttraumatic stress disorder (PTSD) treatments are not effective for the treatment of moral injury and that individuals who have experienced morally injurious events may respond differently to treatment than those who have not. However, these claims have yet to be empirically tested. Objective: This study evaluated the rates of morally injurious event exposure and morally injurious index trauma and their impact on PTSD (PCL-5) and depression symptom (PHQ-9) reductions during intensive PTSD treatment. Method: Data from 161 USA military combat service members and veterans (91.3% male; mean age = 39.94 years) who participated in a 3-week Cognitive Processing Therapy (CPT)-based intensive PTSD treatment programme (ITP) was utilized. Morally injurious event exposure was established via the Moral Injury Event Scale (MIES). Index traumas were also coded by the treating clinician. Linear mixed effects regression analyses were conducted to examine if differences in average effects or trends over the course of treatment existed between veterans with morally injurious event exposure or index trauma and those without. Results: Rates of morally injurious event exposure in this treatment sample were high (59.0%-75.2%). Morally injurious event exposure and the type of index trauma did not predict changes in symptom outcomes from the ITP and veterans reported large reductions in PTSD (d = 1.35–1.96) and depression symptoms (d = 0.95–1.24) from pre- to post-treatment. Non-inferiority analyses also demonstrated equivalence across those with and without morally injurious event exposure and index events. There were no significant gender differences. Conclusions: The present study suggests that PTSD and depression in military veterans with morally injurious event exposure histories may be successfully treated via a 3-week CPT-based ITP.

414. Association of SARS-CoV-2 Genomic Load Trends with Clinical Status in COVID-19:A Retrospective Analysis from an Academic Hospital Center in New York City

BackgroundThe Infectious Diseases Society of America has identified the potential use of SARS-CoV-2 genomic load for prognostication purposes as a key research question.MethodsWe designed a retrospective cohort study that included adult patients with COVID-19 pneumonia who had at least 2 positive nasopharyngeal tests at least 24 hours apart to study the correlation between the change in the genomic load of SARS-CoV-2 in nasopharyngeal samples, as reflected by the Cycle threshold (Ct) value of the real-time Polymerase Chain Reaction (PCR) assay, with change in clinical status. The Sequential Organ Failure Assessment (SOFA) score was used as a surrogate for patients’ clinical status. A linear mixed-effects regression analysis was performed.ResultsAmong 457 patients who presented to the emergency department between 3/31/2020- 4/10/2020, we identified 42 patients who met the inclusion criteria. The median initial SOFA score was 2 (IQR 2–3). 20 out of 42 patients had a lower SOFA score on their subsequent tests. We identified a statistically significant inverse correlation between the change in SOFA score and change in the Ct value with a decrease in SOFA score by 0.05 (SE 0.02; p < 0.05) for an increase in Ct values by 1. This correlation was independent of the duration of symptoms.Flow chart A graph of the Cycle Threshold (Ct) values of the of Cepheid Xpert® Xpress SARS-CoV-2 assay measured on repeat screening of the 42 included patients. Graph of the fitted SOFA scores based on the Cycle Threshold values per patient. ConclusionOur findings suggest that an increasing Ct value in sequential tests may be of prognostic value for patients diagnosed with COVID-19 pneumonia. Before repeat testing can be recommended routinely in clinical practice as a predictor of disease outcomes, prospective studies with a standardized interval between repeat tests should confirm our findings.Disclosures All Authors: No reported disclosures

Change in Viral Load Count and Its Predictors Among Unsuppressed Viral Load Patients Receiving an Enhanced Adherence Counseling Intervention at Three Hospitals in Northern Ethiopia: An Exploratory Retrospective Follow-Up Study.

BackgroundEnhanced adherence counseling (EAC) is an interventional program that provides targeted adherence counseling for unsuppressed viral load people living with HIV who are receiving antiretroviral therapy before diagnosing treatment failure. However, there is a lack of evidence on change in viral load count among patients receiving EAC intervention. Therefore, this study aimed to assess change in viral load count and its predictors among people living with HIV (PLHIV) in northeast Ethiopia.MethodsA hospital-based retrospective follow-up study was conducted on 235 randomly selected patients with unsuppressed viral load who started EAC sessions between 2016 and 2019 at three governmental hospitals in the northern part of Ethiopia. Viral load count and patient individual factors were assessed at EAC program enrollment and viral load counts repeated at the end of EAC session. The main outcome variable was a change in viral load count during the EAC session period. A paired sample t-test was used to determine the mean difference in viral load count before and after EAC intervention. Linear mixed-effects models were used to assess the effect of selected factors on viral load count change.ResultsBased on the paired sample t-test, there was a significant mean difference in viral load count before and after EAC intervention (mean difference=16,904, (95% CI: 9986–23,821; p-value<0.001). The multivariable linear mixed-effects regression analysis showed that young age (β= 0.03; 95% CI: 0.01, 0.14), urban residence (β= −0.55; 95% CI: −0.63, −0.34), CD4 count of 201–500 cells/mm3 (β= −0.67; 95% CI: −0.87, −0.43) and long duration on ART (β= −0.01; 95% CI: −0.01, −0.02) were associated with the decline in viral load count.ConclusionWe detected a substantial decline in viral load count among patients receiving an EAC intervention. Young age, urban residence, CD4 count of 201–500 cells/mm3 and long duration on ART were the positive predictors of viral load suppression.

Gender Effects in Assessment of Clinical Teaching: Does Concordance Matter?

Gender bias is thought to exist in the assessment of clinical teachers, yet its extent in different specialties is not well-documented nor has it been studied at the individual-dyadic level. The authors sought to determine whether gender bias exists in residents' assessments of faculty teaching in 3 clinical departments, and if present, whether this is influenced by gender concordance or discordance between the faculty and resident. Residents' ratings of faculty in internal medicine (800 faculty, 5753 ratings), surgery (377, 2249), and family medicine (672, 3438) at the University of Toronto from 2016-2017 were analyzed using the overall global rating on a 5-point scale. A mixed-effects linear regression analysis accounted for nesting of ratings within each faculty member. Overall scores of teaching effectiveness showed a strong skew to favorable ratings for all faculty and a ceiling effect. However, gender effects differed across departments. In internal medicine (38.5% female faculty), no significant gender effects were detected. In surgery (16.2% female) and family medicine (53.0% female), male faculty received significantly higher scores than female faculty. In surgery this was driven by male residents giving male faculty higher ratings (4.46 vs 4.26, P < .001). In family medicine this was driven by male faculty receiving higher ratings regardless of resident gender (4.65 to 4.57, P < .001). Although effects were very small and inconsistent, with gender concordance mattering only for one department, it suggests that gender is a meaningful source of variance in teaching assessments.

Effect of PM2.5 for hospitalization of cardiovascular diseases and medical expenses by age group: a nationwide study from the Japanese Registry Of All cardiac and vascular Diseases (JROAD)

Abstract Introduction Although particulate matter with an aerodynamic diameter less than or equal to 2.5 μm (PM2.5) exposure influences cardiovascular events, there is limited knowledge how PM2.5 exposure is associated with cardiovascular hospitalization in Japan. Purpose We tested the hypothesis that PM2.5 exposure was related to the number of cardiovascular hospitalizations, hospitalization period, and medical expenses. Methods We included 835,405 subjects who were admitted to acute care hospitals in Japan. We classified PM2.5 exposure concentration into quintile groups (from low to high in the order of “PM-1” to “PM-5” group). Multilevel mixed-effects Poisson and linear regression analysis were used to estimate the association of PM2.5 exposure concentration with the cardiovascular hospitalization events, duration and medical expenses. We also analyzed those factors classified by age. Results PM-2, 3, 4, 5 group were positively related to the number of cardiovascular hospitalization events compared with PM-1 group (Table 1). PM-3, 4, 5 group were positively associated with a 0.018, 0.029, and 0.029 (all p&amp;lt;0.001) of the difference of log cardiovascular hospitalization period compared with PM-1 group (p for trend &amp;lt;0.001). These groups were also positively associated with a 0.016, 0.023, and 0.021 (all p&amp;lt;0.001) of the difference of log medical expenses compared with PM-1 group (p for trend &amp;lt;0.001). Analyzed by age group, hospitalization duration was longer (p&amp;lt;0.05) and medical expenses was lower (p&amp;lt;0.05) significantly in super-aging group (over 90 years old) than the group under 64 years old (Figure 1). Conclusions PM2.5 exposure concentration has harmful effect on not only cardiovascular events but cardiovascular hospitalization period and medical expenses due to big-data in Japan. Medical costs were kept low in comparison with their hospitalization period in subjects over 90 years old. Figure 1 Funding Acknowledgement Type of funding source: None

Effect of evening light exposure on sleep in bipolar disorder: A longitudinal analysis for repeated measures in the APPLE cohort.

Sleep disturbance, a core feature of bipolar disorder, is associated with residual mood symptoms, mood episode recurrence and suicide ideation. We investigated the effect of evening light exposure on sleep in patients with bipolar disorder. In this longitudinal analysis, we measured the sleep parameters of 207 outpatients with bipolar disorder using actigraphy at their homes for seven consecutive nights. We measured the white-light illuminance and the irradiance of each wavelength during the 4 hours before each participant's bedtime. We used mixed-effect linear regression analysis for repeated measures to evaluate the effect of evening light exposure on subsequent sleep parameters. The median white-light illuminance was 25.8 lux (interquartile range, 12.9-50.1 lux). In a multivariable model adjusted for potential confounders, we found higher white-light illuminance to be significantly associated with lower sleep efficiency (per log lux: 95% confidence interval = [-1.328, -0.133]; p = 0.017), prolonged sleep-onset latency (95% confidence interval = [0.006, 0.172]; p = 0.035) and longer wake after sleep onset (95% confidence interval = [1.104, 4.459]; p = 0.001). This effect size was larger in the younger age group (aged < 44 years) stratified by median age. Higher irradiance of the blue wavelength range was significantly associated with longer wake after sleep onset, a result similar to those for the green and red wavelength ranges. We observed significant associations between evening light exposure and subsequent sleep in patients with bipolar disorder. The effects of various light wavelengths on sleep in bipolar disorder require further investigation.

Metabolomics signatures of the short-term exposure to air pollution and temperature

Background/Aim:Short-term exposures to air pollution and temperature have been reported to be associated with inflammation and oxidative stress. However, mechanistic understanding of the affected metabolic pathways is still lacking and the existing literature on the short-term exposure of air-pollution on the metabolome is limited. We aimed to determine the changes in the blood metabolome and the associated pathways related to short-term exposure to outdoor air pollution and temperature. Methods:We performed mass-spectrometry based untargeted metabolomic profiling of plasma samples from a large and well-characterized cohort of men (the Normative Aging Study) to identify metabolic pathways associated with short-term exposure to PM2.5, NO2, O3, and temperature (one, seven-, and thirty-day average of central site monitors). We used multivariable linear mixed-effect regression and independent component analysis (ICA) while simultaneously adjusting for all exposures and correcting for multiple testing. Results:Overall, 456 white men provided 648 blood samples, in which 1,158 metabolites were quantified, between 2000 and 2016. Average age and body mass index were 75.0 years and 27.7 kg/m2, respectively. Only 3% were current smokers. In the adjusted models, PM2.5, NO2, and temperature showed multiple statistically significant associations with several metabolites (40 metabolites for PM2.5, 100 metabolites for NO2, 1 metabolite for O3, and 14 metabolites for temperature). We identified eight metabolic pathways (glycerophospholipid, sphingolipid, glutathione, beta-alanine, pyrimidine, butanoate, propanoate, and methionine, cysteine, SAM and taurine metabolisms) perturbed with short-term exposure to air pollution and temperature. These pathways were involved in inflammation and oxidative stress, immunity, and nucleic acid damage and repair. Conclusions:We identified several significant metabolites and metabolic pathways associated with short-term exposure to air pollution and temperature; using an untargeted approach. This is the first study to report an untargeted metabolomic signature of temperature exposure, the first to use ICA, and the largest study to derive a metabolomic signature of air pollution.

Reduced mesiodistal tooth dimension in individuals with osteogenesis imperfecta: a cross-sectional study

Objective Osteogenesis imperfecta (OI) is a rare, hereditary disease affecting collagen type-1 in connective tissue. Collagen type-1 is a substantial component of dentine, and it is speculated, whether affected dentine could cause altered mesiodistal tooth dimension possibly affecting restorative treatment regimen. Therefore, the aim of the present study was to measure mesiodistal tooth dimensions in individuals with OI and compare them with healthy controls. Materials and methods Fifty-seven individuals aged 20–77 years with OI type 1–4 were included and 70 control patients aged 11–34 years were drawn from an orthodontic database. Mesiodistal tooth dimensions of all tooth types, except third molars, were measured in mm (two decimals) on digital 3 D-models of the tooth-bearing arches. Results Multilevel mixed-effects linear regression analysis showed that mesiodistal tooth dimension on average was 0.17 mm (95% CI = (−0.33; −0.01)) reduced for the OI group compared to controls. The analysis revealed variation between tooth types; incisors and first premolars were most affected and molars minimally affected. Conclusions The mesiodistal tooth dimension in individuals diagnosed with OI is significantly smaller compared to healthy controls, which should be taken into consideration in the restorative treatment planning of individuals with OI, although the magnitude of the deviation is relatively small. The results on mesiodistal tooth dimensions of the present controls may be used as a standard for comparisons in future studies on tooth dimensions.

Combination Radiation Therapy and PARP Inhibition Enhances Responsiveness To Anti-PD-1 Therapy In Colorectal Tumor Models

The role of T-cell checkpoint blockade remains limited in colorectal cancer to patients with microsatellite instable-mutated (MSI) disease. Radiation (RT) and PARP inhibition have separately been shown to enhance anti-tumoral immunity when combined with T-cell checkpoint inhibitors. Therefore, we hypothesized that RT and PARP-inhibition would promote a pro-immunogenic tumor microenvironment and enhance the in vivo efficacy of anti-PD-1 therapy in colorectal tumor models. We utilized CT26 and MC38 which represent validated murine models of microsatellite stable (MSS) and MSI-mutated tumors, respectively. The radiosensitization was assessed using clonogenic survival assays. Surface localization of MHC-1, PD-L1, and calreticulin were assessed 24 hours after treatment with RT +/- veliparib using FLOW cytometry. Expression of inflammatory and immunosuppressive cytokines including IFN-γ, CXCL10, IL6, and TGF-β were assessed using PCR at 1, 3, and 7 days after treatment with RT +/- veliparib. In vivo efficacy of combination therapy was assessed using unilateral flank tumor models treated with RT (8 Gy x 2) +/- veliparib (BID x 7 days) +/- anti-PD-1 antibody (x3 doses). T-cell depletion was achieved using an anti-CD8 antibody administered 3 x weekly. In vitro effects were analyzed using 1- and 2-way ANOVAs and in vivo tumor growth delay was analyze using mixed effect linear regression analyses. We identified veliparib as a potent radiosensitizer in both cell lines. Radiation dose-dependently increased MHC-1 and PD-L1 surface localization and this effect was enhanced with veliparib pretreatment in both cell lines. High-dose RT significantly increased delayed expression of INF-γ and CXCL-10 and veliparib pretreatment significantly enhanced these effects. Neither veliparib nor RT affected expression of TGF-β or IL-6 at any timepoint. Concurrent administration of veliparib and subablative RT (8 Gy x 2) significantly extended in vivo anti-PD-1 mediated tumor growth delay and survival in both tumor models. Moreover, these effects were greater in the MSI-mutated MC38 tumor model. Enhancement of anti-PD-1 mediated tumor growth delay with veliparib and RT was attenuated by CD8+ T-cell depletion. We provide preclinical evidence of a novel therapeutic approach to enhance local responsiveness to checkpoint inhibitors in both MSS and MSI colorectal cancers. Enhanced local tumor control with RT, PARP inhibition, and anti-PD-1 therapy could provide clinically meaningful benefits for patients with locally-advanced rectal cancer which could be readily tested in prospective clinical trials.

Physical activity assessment by accelerometry in people with heart failure

BackgroundInternational guidelines for physical activity recommend at least 150 min per week of moderate-to-vigorous physical activity (MVPA) for adults, including those with cardiac disease. There is yet to be consensus on the most appropriate way to categorise raw accelerometer data into behaviourally relevant metrics such as intensity, especially in chronic disease populations. Therefore the aim of this study was to estimate acceleration values corresponding to inactivity and MVPA during daily living activities of patients with heart failure (HF), via calibration with oxygen consumption (VO2) and to compare these values to previously published, commonly applied PA intensity thresholds which are based on healthy adults.MethodsTwenty-two adults with HF (mean age 71 ± 14 years) undertook a range of daily living activities (including laying down, sitting, standing and walking) whilst measuring PA via wrist- and hip-worn accelerometers and VO2 via indirect calorimetry. Raw accelerometer output was used to compute PA in units of milligravity (mg). Energy expenditure across each of the activities was converted into measured METs (VO2/resting metabolic rate) and standard METs (VO2/3.5 ml/kg/min). PA energy costs were also compared with predicted METs in the compendium of physical activities. Location specific activity intensity thresholds were established via multilevel mixed effects linear regression and receiver operator characteristic curve analysis. A leave-one-out method was used to cross-validate the thresholds.ResultsAccelerometer values corresponding with intensity thresholds for inactivity (< 1.5METs) and MVPA (≥3.0METs) were > 50% lower than previously published intensity thresholds for both wrists and waist accelerometers (inactivity: 16.7 to 18.6 mg versus 45.8 mg; MVPA: 43.1 to 49.0 mg versus 93.2 to 100 mg). Measured METs were higher than both standard METs (34–35%) and predicted METs (45–105%) across all standing and walking activities.ConclusionHF specific accelerometer intensity thresholds for inactivity and MVPA are lower than previously published thresholds based on healthy adults, due to lower resting metabolic rate and greater energy expenditure during daily living activities for HF patients.Trial registrationClinical trials.gov NCT03659877, retrospectively registered on September 6th 2018.

Abstinence-reinforcing contingency management improves HIV viral load suppression among HIV-infected people who use drugs: A randomized controlled trial

BackgroundHIV-infected people who use drugs (PWUD) have poor HIV outcomes. Few studies tested interventions to improve HIV outcomes among PWUD. Abstinence-reinforcing contingency management (CM) reduces drug use and could also improve HIV outcomes. MethodsFrom 2012–2017, we conducted a randomized controlled trial testing whether a 16-week abstinence-reinforcing CM intervention improved HIV viral load (VL) among HIV-infected adults using opioids or cocaine. In the CM intervention, drug-free urines led to escalating value of vouchers ($2.50-$80/voucher, $1320 total maximum). In intention-to-treat mixed-effects linear and logistic regression analyses, we examined whether the CM intervention improved log10 VL (primary outcome), abstinence and antiretroviral adherence (secondary outcomes). ResultsThirty-seven participants were randomized to the CM intervention and 36 to control. Median age was 49.2 years; most were male (61.6%) and non-Hispanic black (46.6%). In CM (vs. control) participants, mean reduction in log10 VL was greater (−0.16 log10 VL copies/mL per 4-week period; 95% CI: −0.29 to −0.03, p < 0.05). Over 16 weeks, CM participants had a mean reduction of 0.64 copies/mL in log10 VL greater than control participants. The CM intervention was not significantly associated with abstinence or adherence. ConclusionsThis is the first study to demonstrate improvements in HIV VL via an abstinence-reinforcing CM intervention. Because the CM intervention did not significantly affect abstinence or adherence, the mechanism of its effect is unclear. To end the HIV epidemic, innovative strategies must address individuals with poor HIV outcomes. Abstinence-reinforcing CM may be one potential strategy to improve HIV outcomes among a select group of PWUD.